Device for forming a medical paste

ABSTRACT

The invention regards a device for reconstituting a bioactive agent and forming a flowable paste, the device comprising: —a base configured for receiving: —a first container containing a liquid, and —a second container containing the bioactive agent, —a syringe containing a paste forming material, the syringe being attachable to the base, wherein the base has a first conduit for fluidly connecting the first container with the second container and a second conduit for fluidly connecting the second container with the syringe, and wherein the first container is configured to be pressurizable such that when the first and second containers are received at the base, the liquid is forced through the first conduit into the second container, thereby reconstituting the bioactive agent, and the reconstituted bioactive agent is forced through the second conduit into the syringe, such that a paste is formed.

This application is the U.S. National Stage of International ApplicationNo. PCT/EP2019/067018, filed Jun. 26, 2019, which designates the U.S.,published in English, and claims priority under 35 U.S.C. § 119 or365(c) to EP Application No. 18180033.5, filed Jun. 27, 2018. The entireteachings of the above applications are incorporated herein byreference.

FIELD OF INVENTION

The present invention relates to a device, a kit of parts, and a methodfor forming a medical paste, such as a device and method forreconstituting a bioactive agent and for forming a flowable paste in asyringe.

BACKGROUND OF INVENTION

A paste may be precisely applied to a target site by use of a syringe. Asyringe comprises a plunger, or piston, fitted to a barrel with anopening, where the barrel comprises the paste. By pushing or translatingthe syringe plunger along the barrel, the paste being in the form of anessentially non-compressible thick viscous composition, is dischargedfrom the opening of the syringe barrel in a controlled manner. Thus, apaste may be delivered to a target site with high spatial precision andin a flexible dosage, by use of a syringe.

The delivery of a paste to a specific target site and in a preciseamount, is essential for pastes, which are applied for medical purposes,such as for surgical applications. For example, haemostatic compositionsfor surgical applications are typically in the form of a paste.

An example of an effective surgical haemostat is a gelatine pastecomprising a haemostatically effective amount of thrombin. Thrombin is aclotting agent, and may thus be used to control the bleeding at ahaemorrhaging site. However, for the medical paste to be haemostaticallyefficient, it is essential that an effective concentration of thethrombin is present in the paste, that the thrombin is uniformlydistributed in the paste, and that the paste has a suitable viscosityand rheology for precise and fixed positioning.

Thus, to obtain an efficient medical paste, the step of manufacturingthe paste with sufficient uniform distribution of the agents, as well ascorrect concentration of the bioactive agent, and correct ratio betweenthe components, is essential.

The efficiency of the paste will also depend on the paste storage timeafter preparation, since the paste consistency or rheology may degradeover time, and also the efficiency of the bioactive agent may degradeover time due to chemical instability. For most bioactive agents, thestorage stable form is the dry state, and storage in a paste or otherliquid states are usually not storage stable forms. The dry bioactiveagent may be reconstituted to a liquid form by mixing with a liquid.

To ensure the quality and efficiency of the paste, medical pastes aretypically prepared on-site and immediately prior to use. The on-sitepreparation demands high precision of the person preparing the paste,who typically is under time pressure during the surgical procedure.Thus, the step of preparing the paste involves a risk of incorrectconcentration dosages of the bioactive agent, and insufficient mixing ofthe paste.

Mixing procedures and manipulations of different substances can be timeconsuming. In an Operation Room (OR) setting this time consumption maybe critical when using a haemostatic paste for inhibiting bleedings asthe surgeon will have to interrupt his procedure while waiting for thehaemostat. Thus, the preparation time of the paste may cause increasedblood loss and longer operating time of the surgical procedure.

Mixing substances from different containers may also potentiallycompromise the sterility of the haemostatic paste and can negativelyaffect the consistency of the haemostatic paste if not done correctly. Acorrect paste consistency is important for a satisfactory haemostaticeffect.

To minimize the risk of erroneously mixed pastes, and the associatedwaste of bioactive agent and inefficient treatment of the patient, andto reduce the paste preparation time, there is a need for a pastepreparation that is more efficient, such as includes partly or fullyautomated steps.

WO 10/043685 [1] discloses a device for mixing two substances, such asan active powdered drug and a diluent. The two substances are initiallystored in two separate compartments, and they are mixed upon generatinga fluid flow between the two compartments. The driving force forgenerating the fluid flow may be a pre-established positive pressure inthe first container. Thus, an exact diluent to drug ratio is obtained inthe mixed product. The mixed material may be retrieved to a syringe, andadministered to the body by e.g. injection or infusion.

Despite the advances in the field, there is a need for more simple,efficient, and reliable devices and methods for preparing medicalmixtures, such as medical pastes.

SUMMARY OF INVENTION

The present invention provides a device, a kit of parts, and a methodfor a more simple, efficient, and reliable preparation of a medicalpaste. Advantageously, the medical paste is produced directly in asyringe. Thus, for example the device and method may be used for fast,easy, convenient, and reliable reconstitution of a bioactive agent, suchas a lyophilized drug, with a liquid or diluent, and a paste formingmaterial, usually in the form of a biocompatible polymer, to form aflowable haemostatic matrix for use in surgical procedures. Thus, thedevice and process may result in improved surgical procedures, includinglimited blood loss and lower operating time of the surgical procedures.

The present invention is surprisingly suitable for the incorporation ofthrombin in haemostatic pastes, and facilitates that a haemostatic pastecomprising thrombin may be generated in a single step operation. Suchsimple and fast method for preparing a haemostatic composition is highlyvaluable in the operating room where potential bleeding must becontrolled in a fast and efficient manner.

A first aspect of the invention relates to a device for reconstituting abioactive agent and forming a paste, the device comprising:

-   -   a base configured for receiving:        -   a first container containing a liquid, and        -   a second container containing the bioactive agent,    -   a syringe containing a paste forming material, the syringe being        attachable to the base.

The base preferably has a first conduit for fluidly connecting the firstcontainer with the second container and a second conduit for fluidlyconnecting the second container with the syringe.

Advantageously the first container is configured to be pressurizablesuch that when the first and second containers are received at the base,the liquid is forced through the first conduit into the secondcontainer, thereby reconstituting the bioactive agent, and thereconstituted bioactive agent is forced through the second conduit intothe syringe, such that a paste is formed.

Further advantageously, the first container is pressurized by liquidpressure, or by compression, optionally elastic deformation, of thecontainer.

In a preferred embodiment, the paste is formed directly in the syringe.In a further preferred embodiment the paste is flowable.

A second aspect of the invention relates to a kit of parts for thedevice according to the first aspect, comprising a base, a syringecontaining a paste forming material, a first container containing aliquid, and a second container containing a bioactive agent.

A third aspect of the invention relates to a method for reconstituting abioactive agent and forming a paste, the method comprising:

-   -   providing a first container containing a liquid under positive        pressure,    -   providing a second container containing the bioactive agent,    -   providing a syringe containing a paste forming material.        Preferably fluidly connecting the first container with the        second container and fluidly connecting the second container        with the syringe such that the liquid is forced from the first        container into the second container, thereby reconstituting the        bioactive agent, and the reconstituted bioactive agent is forced        from the second container into the syringe, such that a paste is        formed.

A fourth aspect of the invention relates to a method according to thethird aspect, configured to be carried out using the device according tothe first aspect or the kit according to the second aspect.

A fifth aspect of the invention relates to use of the device accordingto the first aspect or the kit according to the second aspect for themethod according to the third aspect.

DESCRIPTION OF DRAWINGS

The invention will in the following be described in greater detail withreference to the accompanying drawings.

FIG. 1 shows an embodiment of the device according to the presentdisclosure for reconstituting a bioactive agent and forming a flowablepaste in a syringe, where the first container is pressurized by liquidpressure. The device of FIG. 1 is shown in a configuration before thefirst and second containers are received at the base, and theconnections to the base conduits are formed.

FIG. 2 shows an embodiment of the device of FIG. 1 , when the first andsecond containers are received at the base and the connections to theconduits are formed.

FIG. 3 shows an embodiment of the device of FIGS. 1-2 , when the liquidof the first container has been uniformly mixed with the bioactive agentto form a reconstituted agent 4 c.

FIG. 4 shows an embodiment of the device of FIGS. 1-3 , when thereconstituted bioactive agent has been uniformly mixed with the pasteforming material pre-loaded in the syringe, thereby forming a flowablepaste 5 c in the syringe.

FIG. 5 shows an embodiment of a syringe including a flowable paste,which has been detached from the base, and which is ready fordischarging the paste at a target site.

FIG. 6 shows an embodiment of a kit of parts for assembling the deviceof FIGS. 1-4 .

FIG. 7 shows an embodiment of the device according to the presentdisclosure for reconstituting a bioactive agent and forming a flowablepaste in a syringe, where the first container is pressurized by elasticdeformation. (A) shows the configuration before the first and secondcontainers are received at the base, and the connections to the baseconduits are formed. (B) shows the configuration when the first andsecond containers are received at the base and the connections to theconduits are formed.

DETAILED DESCRIPTION OF THE INVENTION

The invention is described below with the help of the accompanyingfigures. It would be appreciated by the people skilled in the art thatthe same feature of component of the device are referred with the samereference numeral in different figures. A list of the reference numberscan be found at the end of the detailed description section.

The present disclosure relates to a device, a kit, and a method forforming a medical paste directly in a syringe. Subsequently, the medicalpaste may be discharged from the syringe, and delivered to a target sitewith high spatial precision and in a flexible dosage.

More specifically, the present disclosure relates to a device, a kit,and a method for forming a medical paste spontaneously and automaticallyin a syringe. The medical paste is formed spontaneously when thecontainers are received at the base. Thus, the medical paste may begenerated in a single step operation, where the single step is aninitiation step, such as the assembly and receival at the base.

Driving Force

The term “spontaneous” is used to describe phenomena arising frominternal forces or causes, which are independent of external agencies orstimuli and which happen within a short period of time, i.e. preferablywithin less than about 30 seconds, more preferred within less than about20 seconds, even more preferred within less than about 10 seconds orwithin less than about 5 seconds, such as within less than about 3seconds, for example less than about 2 seconds.

The spontaneous formation of the paste is triggered by a containerconfigured to be pressurizable. A pressurized container may becharacterized as having pressure energy stored, where the pressureenergy may be converted to kinetic energy by releasing the pressure,e.g. upon manually opening the container, or piercing the container. Thepressurized container may contain a fluid, and the fluid is dischargedfrom the container simultaneously as the pressure is released, as isknown from pressurized beverages.

When the discharged fluid is released into a second container, thedischarged fluid will be mixed with the materials of the secondcontainer due to the released kinetic energy and turbulent flow.However, the degree of mixing, and thus the uniformity of the resultingmixture, will depend on the pressure energy, the viscosity of thedischarged fluid, and the viscosity of the material in the secondcontainer. The higher the viscosity of the second container material,the more energy is needed for producing a uniform mixture.

If the discharged fluid is a liquid, and the second container materialis a fluid, a low amount of energy is needed for forming a uniformmixture between the two fluids. If on the other hand the the dischargedfluid is a liquid and the second container material is a paste, moreenergy is needed for forming a uniform mixture between the fluid and thepaste component. The second container material may also be a solid, suchas particles of powder. In this case, the fluid solubility and/or theability of the fluid to suspend the solid particles, in addition to thekinetic energy, will affect the ability to form a uniform mixturebetween the solid and the discharged fluid.

It was surprisingly found that sufficient reconstitution of a bioactiveagent, and further sufficient mixing of the reconstituted agent to forma uniform paste may be obtained with the kit and device according to thepresent disclosure, where the paste is generated in a single stepoperation. Thus, the device provides a self-containing system forspontaneously forming a medical paste in a single step operation.

Medical Paste

Advantageously, the device and kit according to the present disclosureis applied for producing and mixing a medical paste. By the term“medical paste” is meant a paste comprising a bioactive agent. Anexample of a bioactive agent is thrombin.

A “bioactive agent” is defined as any agent, drug, compound, compositionof matter or mixture which provides some pharmacologic, oftenbeneficial, effect that can be demonstrated in vivo or in vitro. Anagent is thus considered bioactive if it has interaction with or effecton a cell tissue in the human or animal body. As used herein, this termfurther includes any physiologically or pharmacologically activesubstance that produces a localized or systemic effect in an individual.Bioactive agents may be a protein, such as an enzyme. Further examplesof bioactive agents include, but are not limited to, agents comprisingor consisting of an oligosaccharide, a polysaccharide, an optionallyglycosylated peptide, an optionally glycosylated polypeptide, anoligonucleotide, a polynucleotide, a lipid, a fatty acid, a fatty acidester and secondary metabolites. It may be used either prophylactically,therapeutically, in connection with treatment of an individual, such asa human or any other animal. The term “bioactive agent” as used hereindoes not encompass cells, such as eukaryotic or prokaryotic cells.

A “paste” according to the present disclosure has a malleable,putty-like consistency, such as toothpaste. A paste is a thick fluidmixture of pulverized solid/solid in powder form with a liquid. A pasteis a substance that behaves as a solid until a sufficiently large loador stress is applied, at which point it flows like a fluid, i.e. a pasteis flowable. Flowables conform efficiently to irregular surfaces uponapplication. Pastes typically consist of a suspension of granularmaterial in a background fluid. The individual grains are jammedtogether like sand on a beach, forming a disordered, glassy or amorphousstructure, and giving pastes their solid-like character. It is this“jamming together” that gives pastes some of their most unusualproperties; this causes a paste to demonstrate properties of fragilematter. A paste is not a gel/jelly. A “slurry” is a fluid mixture of apowdered/pulverized solid with a liquid, such as water. Slurries behavein some ways like thick fluids, flowing under gravity and being capableof being pumped if not too thick. A slurry may functionally be regardedas a thin, watery paste, but a slurry generally contains more water thana paste. Substantially water-insoluble powder particles, such ascross-linked gelatine particles, will form a paste upon mixing with anaqueous medium.

A “gel” is a solid, jelly-like material that can have properties rangingfrom soft and weak to hard and tough. Gels are defined as asubstantially dilute cross-linked system, which exhibits no flow when inthe steady-state. By weight, gels are mostly liquid, yet they behavelike solids due to a three-dimensional cross-linked network within theliquid. It is the crosslinks within the fluid that give a gel itsstructure (hardness) and contribute to stickiness (tack). In this waygels are a dispersion of molecules of a liquid within a solid in whichthe solid is the continuous phase and the liquid is the discontinuousphase. A gel is not a paste or slurry. For example, non-crosslinkedgelatine is soluble and forms a gel upon contact with an aqueous mediumsuch as water.

For a medical paste to be discharged from a syringe, it should beflowable when subjected to a force applicable for a syringe. Thus, bythe term “flowable paste” is meant a paste having a viscosityfacilitating a steady flow, when subjected to a force applicable for asyringe. An example of a flowable paste is a paste having a viscositybetween 500-3500 Pas, when measured at 30° C. and a relative humiditybetween 65-75%.

In an embodiment of the disclosure, the paste is flowable.

Forming a medical paste, such as a flowable medical paste, requiresmixing of the bioactive agent with a paste or a paste forming material.Typically, bioactive agents are stored in a solid and dried state, suchas a powdered form, facilitating stable storage of the active agent, andflexible concentrations by mixing the bioactive agent with a diluent inan adjustable ratio. Thus, for the bioactive agent to be administered bya syringe injection, the solid bioactive agent must first bereconstituted. Forming a medical paste therefore typically requires thesteps of mixing a solid bioactive agent with a liquid or diluent toreconstitute the bioactive agent, and subsequently mixing thereconstituted bioactive agent with a paste forming material, which mayalso be referred to as a “paste precursor”.

By the term “paste forming material” is meant a material for forming apaste from a liquid phase, such as a reconstituted bioactive agent.Thus, a paste forming material may also be referred to as a precursormaterial for forming a paste.

The reconstituted bioactive agent is obtained by mixing the bioactiveagent with a liquid with low viscosity, such as sterile water or salinewater, thereby ensuring uniform reconstitution. Thus, the reconstitutedbioactive agent is a liquid with low viscosity. A paste may be obtainedfrom the reconstituted bioactive agent by adding a paste formingmaterial, which inherently increases the viscosity.

Mixing Device

The present disclosure relates to a novel way of reconstituting abioactive agent and forming a flowable paste in a syringe. FIG. 1 showsan embodiment of the device for the purpose, prior to the initiatingstep and initiating the reconstitution process. The device 1 comprises abase 2 and a syringe 5. The syringe is detachably attached to the basee.g. by a locking mechanism, and the syringe is further pre-loaded witha paste forming material 5 a. For example, the syringe may be mounted inthe base station by a threaded screwing mechanism, prior to initiatingthe reconstitution process.

The base is configured for receiving two containers: a first container 3containing a liquid 3 a, and a second container 4 containing a bioactiveagent 4 a. A typically bioactive agent is supplied in a solid and drystate, and the bioactive agent may therefore at least partly adhere tothe bottom of the container as illustrated in FIG. 1 . The base of FIG.1 further comprises two conduits: a first conduit 6 and a second conduit7, configured such that when the first and second containers arereceived at the base, the first conduit forms a fluid connection betweenthe first container and the second container, and the second conduitforms a fluid connection between the second container and the syringe.Thus, when the first and second containers are received at the base, theconnections to the conduits are formed.

The first container of FIG. 1 is configured to be pressurizable, andthereby containing a positive pressure, such that when the first andsecond containers are received at the base and the connection to theconduit is formed, the positive pressure forces the liquid out of thefirst container, through the first conduit, and into the secondcontainer. The liquid forced by the positive pressure will furtherprovide turbulent flow within the second container, and thus ensure thatthe liquid and bioactive agent is uniformly mixed within the secondcontainer, thereby forming a reconstituted active agent.

FIG. 2 shows an embodiment of the device, when the first and secondcontainers are received at the base and the connections to the conduitsare formed. The initiaing step resulting in the receival at the base maybe obtained by applying a manual pressure as indicated in FIG. 2 . Thecontainers are pushed manually in a direction towards the base, suchthat an opening of the first container 3 b and an opening of the secondcontainer 4 b is brought into contact with the conduits. FIG. 3 showsthe embodiment, when the liquid of the first container 3 a has beenuniformly mixed with the bioactive agent to form a reconstitutedbioactive agent 4 c.

Since the second container, conduits, and syringe of the device have afixed volume and are non-compressible elements, the positive pressure ofthe first container will further force the reconstituted bioactive agent4 c out of the second container, through the second conduit, and intothe syringe, as illustrated in FIG. 4 . The reconstituted bioactiveagent, which is forced by the positive pressure, will further provideturbulent flow within the syringe, and thus ensure that thereconstituted bioactive agent is uniformly mixed with the paste formingmaterial pre-loaded in the syringe. Thus a flowable paste 5 c is formedin the syringe as illustrated in FIG. 4 .

Alternatively, or additionally, the first container may be configured tobe pressurizable by a further pressure, as illustrated in FIG. 7 . Thefurther pressure is activated after the initiation step of assemblingand receiving the containers at the base. The assembly and receival atthe base is obtained by applying a manual force. After the containersare received at the base, a further pressure to the first container maybe generated manually and/or mechanically by compressing the firstcontainer. The compressed volume of the first container, results inpressurized first container, and a positive pressure of the firstcontainer.

FIG. 7 shows an embodiment of the device according to the presentdisclosure for reconstituting a bioactive agent and forming a flowablepaste in a syringe, where the first container is pressurized by afurther pressure, indicated as P*. (A) shows the configuration beforethe first and second containers are received at the base, and theconnections to the base conduits are formed. (B) shows the configurationwhen the first and second containers are received at the base and theconnections to the conduits are formed.

When the containers are received at the base by applying a manual force(shown as P in FIG. 7 ), a further pressure (P*) may be generated by anelastic compression and deformation of the first container. Thedeformation consequently results in a positive pressure in thecontainer. The elastic deformation may be obtained if the container iscollapsible, for example by having an accordion-shaped portion asillustrated in FIG. 7 . The elastic deformation of the container, andthus the volume of the container, may further be controlled by includingan elastic element, such as a spring through which the further pressureis transferred to the first container. The presence of an elasticelement contributes to a controllable and reproducible positivepressure.

Pressure

The positive pressure of the first container facilitates turbulent flowand the mixing of the components. Thus, the distribution of thecomponents within the paste, and the time for producing the paste, willdepend on the size of the positive pressure.

A positive and variable pressure in a liquid container may be obtainedby pressurizing the liquid, for example by an air pressure, or byelastically deforming the container to compress the container volume.However, the higher the pressure, the more costly and the higher themechanical requirements to the container and the device. It was foundthat sufficient mixing and a fast formation of the paste may be obtainedusing a pressure of between 0.1-5 bar.

In an embodiment of the disclosure, the first container is pressurizedto between 0.1-5 bar, more preferably between 1-3 bar, and mostpreferably about 1 bar. In a further embodiment, the first container ispressurized by liquid pressure. In a further embodiment, the liquid is apressurized liquid.

In another and further embodiment, the first container is pressurized bycompression, and optionally elastic deformation. In a furtherembodiment, the first container comprises a collapsible first container,and/or an elastic element, such as a spring, adapted to compress thevolume of the first container.

The syringe including the flowable paste may subsequently be detachedfrom the base, and the paste applied at a target site as illustrated inFIG. 5 . To ensure fast, easy, and reliable attachment and detachment ofthe syringe, the syringe is advantageously attached by detachablefastening means, or detachably attached to the base by a lockingmechanism. Examples of detachable fastening means include a screw,click-on, slide-on, or snap-fit mechanism.

In an embodiment of the disclosure, the syringe is detachably attachedto the base by a locking mechanism, such as a screw, click-on, orslide-on locking mechanism.

The second container, conduits, and syringe have a fixed volume and arenon-compressible elements. Thus, when the positive pressure of the firstcontainer is released, a pressure wave is generated which advancedthrough the device. The pressure wave is therefore the driving force foradvancing the liquid phases into the syringe and for mixing the phases.

To ensure that the pressure wave propagates unidirectional within thedevice, i.e. in a direction going from the first container and into thesyringe, the syringe advantageously comprises a pressure controllingelement 5 b placed in the syringe plunger, as illustrated in FIG. 4 .The pressure controlling element advantageously acts as a pressurereleasing element, such that a backpressure generated within the syringemay be avoided.

The positive pressure of the first container may be obtained by a gas,such as air. Thus advantageously, the pressure controlling element is agas filter, having the function of a gas release valve. As illustratedin FIG. 4 , the air pressure from the first container travels from thefirst container, through the device, and is discharged to thesurroundings at the syringe piston.

The pressure controlling element further provides the advantage thatgasses are not trapped within the syringe, and the risk of deliveringdetrimental gasses exposed to the patient simultaneously with applyingthe paste, is avoided. In addition to the gasses from the firstcontainer, gasses present in the conduits and the second container andsyringe, may be released through a gas filter as illustrated in FIGS.3-4 .

Advantageously, the pressure controlling element is further adapted tofiltrate fluids in the gaseous state (also referred to as gaseousfluids), while retaining fluids in the liquid state (also referred to asliquid fluids). Thus, the pressure controlling element will allow thegasses to pass through the filter and to the surroundings, while theliquid phases (i.e. the paste forming material, the reconstitutedbioactive agent, and the flowable paste) are maintained within thesyringe. An example of a pressure controlling element adapted tofiltrate gaseous fluids, and retaining liquid fluids is a filter withvariable pore size. For example a filter comprising a hydrophobicmaterial may be configured such that the pore size varies depending onthe moisture or water content. Upon exposure to increasing watercontent, the material expands, and thereby decreases the internal poresize. Thus, as long as the filter is exposed to gases, the gases maypass through the filter. However, when the filter is exposed to a liquidphase, the liquid phase cannot pass through.

In an embodiment of the disclosure, the syringe further comprises apressure controlling element. In a further embodiment, the pressurecontrolling element is a filter adapted to filtrate gaseous fluids fromliquid fluids. In a further embodiment, the filter comprises acomposition adapted to be expandable upon contact with water. In afurther embodiment, the filter comprises a hydrophobic material.

It follows from the above description that the device of the presentdisclosure may be considered to have four configurations. The firstconfiguration is illustrated in FIG. 1 , and shows the device before thefirst and second containers are received at the base. The secondconfiguration is illustrated in FIG. 2 and FIG. 7 , and shows the devicewhen the first and second containers are received at the base. The thirdconfiguration is illustrated in FIG. 3 , and shows the device when thebioactive agent is reconstituted. The fourth configuration isillustrated in FIG. 4 , and shows the device when the paste is formed inthe syringe. When the first and second containers are received at thebase, the transition from the first configuration to the fourthconfiguration automatically and spontaneously occurs due to the pressurepresent or generated within the pressurizable first container.

In the first configuration, the first and second containers are mountedin the device, but not received at the base. To minimize the risk ofaccidental receival at the base, e.g. by an accidental push to thedevice during storage or transport, the first and second containers areadvantageously provided as separate units. An embodiment of the kit ofparts is illustrated in FIG. 6 . For fast and easy mounting in thedevice and for easy receival at the base, the first and secondcontainers are advantageously provided as a connected separate unit, asillustrated in FIG. 6 .

In an embodiment of the disclosure, the device is provided as a kit ofparts comprising a base, a syringe containing a paste forming material,a first container containing a liquid, and a second container containinga bioactive agent. In a further embodiment, the kit comprises a syringedetachably attached to a base, and a first and a second containerconnected to each other.

Components

The present disclosure provides a fast, easy, and convenient mixing of aliquid, a bioactive agent, and a paste forming material into a paste,such as a flowable paste. The efficiency of the resulting paste willdepend on the type of components (i.e. type of liquid, bioactive agent,and paste forming material), the degree of mixing of the components, andthe distribution of the components within the paste, as well as theratio between the components.

Bioactive Agent and Liquid

For the flowable paste to act as a haemostatic matrix, the bioactiveagent is advantageously of a type, which acts as a clotting agent, suchas thrombin.

Bioactive agents, such as thrombin, are typically expensive and storedin a solid and/or dried state to ensure chemical stability, longerstorage times, and thus lower material waste. Advantageously thebioactive agent is a lyophilized agent, such as lyophilized thrombin.Lyophilization, is also known as freeze-drying, and involves dehydrationof the bioactive agent, such that it is preserved and stored in a driedsolid state. Thus, lyophilization provides an efficient storage form.However, for the lyophilized bioactive agent to be applied by injection,the lyophilized agent must be reconstituted by mixing with a liquid.

It is known in the art that the storage life of injectable substances,such as thrombin, is increased when the substance is stored in apowdered state. Lyophilization is one way of producing a powderedsubstance from a liquid based material. It involves a rapid freezing ofthe material at a very low temperature followed by a rapid dehydrationby sublimation in a high vacuum.

The resulting lyophilized substance is typically stored in a glass vialor cartridge which is closed by a cap, such as a rubber stopper orseptum. It is necessary to reconstitute the powdered or solid substanceprior to administration. This is accomplished by mixing the powderedsubstance with a suitable diluent or liquid.

Further, to ensure sufficient uniform mixing of the bioactive agentwithin the paste, such that the paste acts as an efficient haemostaticmatrix, the bioactive agent is advantageously reconstituted by a liquidcapable of dissolving the agent or keeping the agent in essential stablesuspension. Further advantageously, the liquid is of a type which actsas a diluent, such that the concentration of the bioactive agent can beeasily adjusted. For example, thrombin may be easily dissolved and/orsuspended by water, sterile water, saline water, sterile saline, or amixture of water and glycerol.

In an embodiment of the disclosure, the bioactive agent is a dried orlyophilized substance. In a further embodiment, the bioactive agentcomprises thrombin. In a further embodiment, the bioactive agentcomprises or consists of lyophilized thrombin.

In one embodiment of the disclosure, the thrombin is recombinantthrombin.

In one embodiment of the disclosure, the thrombin is human thrombin.

In an embodiment of the disclosure, the liquid is a diluent. In afurther embodiment, the liquid is an aqueous medium selected from thegroup of: water, glycerol, sterile water, saline, sterile saline, acalcium chloride solution, a buffered aqueous solution, and combinationsthereof.

Thrombin is added to the paste of the present disclosure in an amountsufficient to ensure effective haemostasis of the paste. In oneembodiment thrombin will be present at a concentration in the range ofabout 100 IU/ml paste to about 500 IU/ml paste, such as about 150 IU/mlpaste to about 450 IU/ml paste, for example about 200 IU/ml paste toabout 400 IU/ml paste, such as about 250 IU/ml paste to about 350 IU/mlpaste.

In one embodiment, thrombin will be present in the paste at aconcentration in the range of about 50 IU/g paste to about 5000 IU/gpaste, preferably between about 100 IU/g paste to about 1000 IU/g paste,such as between about 200 IU/g paste to about 800 IU/g paste.

Reconstitution of a dry preparation of a bioactive agent such asthrombin is traditionally performed using a syringe with a needle towithdraw the diluent from one separate vial and inject it into anotherseparate vial containing the dry thrombin, whereupon the latter vial isshaken or swirled to thoroughly mix the two constituents. The syringewith needle is then used to withdraw from this vial the desired amountof reconstituted bioactive agent. Because two separate containers areused, the person reconstituting the bioactive agent must be certain tomix the correct amounts such that a proper concentration of the mixtureresults.

In the present disclosure, the components are pre-loaded in the syringeand containers in predefined amounts and ratios. Thus, the steps ofmeasuring the correct amount of the components are avoided, and apredefined amount of paste is rapidly, easily, and convenientlyproduced.

Paste Forming Material

To ensure the formation of an effective paste, such as a paste withsufficient flowability to be delivered to a target site by a syringe,and such that the delivered paste may be precisely and fixedlypositioned at the target site, certain paste forming materials andcertain paste compositions (i.e. ratios between the components) werefound advantageous.

Advantageously, the paste forming material comprises a biocompatiblepolymer.

The biocompatible polymer of the present disclosure may be a biologic ora non-biologic polymer. Suitable biologic polymers include proteins,such as gelatine, collagen, albumin, haemoglobin, casein, fibrinogen,fibrin, fibronectin, elastin, keratin, and laminin; or derivatives orcombinations thereof. Particularly preferred is the use of gelatine orcollagen, more preferably gelatine. Other suitable biologic polymersinclude polysaccharides, such as glycosaminoglycans, starch derivatives,xylan, cellulose derivatives, hemicellulose derivatives, agarose,alginate, and chitosan; or derivatives or combinations thereof. Suitablenon-biologic polymers will be selected to be degradable by either of twomechanisms, i.e. (1) break down of the polymeric backbone or (2)degradation of side chains which result in aqueous solubility. Exemplarynonbiologic polymers include synthetics, such as polyacrylates,polymethacrylates, polyacrylamides, polyvinyl resins,polylactide-glycolides, polycaprolactones, and polyoxyethylenes; orderivatives or combinations thereof. Also combinations of differentkinds of polymers are possible.

In one embodiment, the biocompatible polymer is biologically absorbable.Examples of suitable biologically absorbable materials include gelatine,collagen, chitin, chitosan, alginate, cellulose, oxidised cellulose,polyglycolic acid, polyacetic acid and combinations thereof. It will beunderstood that various forms thereof, such as linear or cross-linkedforms, salts, esters and the like are also contemplated for the presentdisclosure. In a preferred embodiment of the invention, the biologicallyabsorbable material is gelatine. Gelatine is preferred since gelatine ishighly biologically absorbable. Furthermore, gelatine is highlybiocompatible, meaning that it is non-toxic to an animal, such as ahuman being, when/if entering the blood stream or being in long-termcontact with human tissues.

The gelatine typically originates from a porcine source, but mayoriginate from other animal sources, such as from bovine or fishsources. The gelatine may also be synthetically made, i.e. made byrecombinant means.

In a preferred embodiment the biocompatible polymer is cross-linked.Cross-linking usually renders the polymer substantially insoluble in anaqueous medium. In one embodiment, the biocompatible polymer consists ofpowder particles which are substantially insoluble in an aqueous medium.Any suitable cross-linking methods known to a person of skill may beused including both chemical and physical cross-linking methods.

In an embodiment of the disclosure, the paste forming material compriseswater-insoluble particles and/or cross-linked particles. In a furtherembodiment, the paste forming material comprises cross-linked gelatineparticles.

The cross-linked powder particles are in one embodiment less thanapproximately 1000 microns in size, i.e. so that they are able to passthrough a 1×1 mm sieve.

Generally at least 90% of the powder particles have a diameter ofbetween 1 μm and 1200 μm.

In one embodiment, the average particle diameter is between 1 μm and1000 μm, such as between 10 μm and 800 μm, for example between 50 μm and600 μm, such as between 100 μm and 500 μm, for example between 200 μmand 400 μm, such as about 300 μm.

In some applications it is desirable to have a smaller particle size,whereby a smoother paste can be obtained. Thus in one embodiment, theaverage particle diameter is less than 100 μm, such as less than 50 μm,for example less than 30 μm, such as less than 20 μm, for example lessthan 10 μm. One example of an application where a smoother paste isdesirable is in the control of bone bleeding.

Particles of a certain size distribution can be achieved by passing apowdered composition through one or more sieves having a certain meshsize and collecting the powder which passes through and/or is retainedby a certain mesh size. For example, powder particles having a sizedistribution between approximately 200 μm and 1000 μm can be obtained bycollecting the powder which is able to pass through a 1×1 mm sieve butis retained by a 0.2×0.2 mm sieve.

In one embodiment, the paste forming material comprises or consists ofcross-linked gelatine particles obtained from a micronized porousgelatine sponge, which has been cross-linked by dry heat treatment.

To further facilitate fast formation of the paste, and fast and uniformmixing between the paste forming material and the reconstitutedbioactive agent, it was found advantageously that the paste formingmaterial is in the form of a solid, such as a dry composition, driedpaste, or a powder. Further advantageously, the powder may be pressedpowder, and shaped into a pellet. Pressed powders or pellets are easilypre-loaded into a syringe, and provides a fixed dosage. Thus, carefulmeasurement of amounts of paste forming material is avoided. The pasteforming material may also be provided as a vacuum expanded dry paste,having a density between about 1 mg/ml to about 40 mg/ml.

In an embodiment of the disclosure, the paste forming material is in theform of a solid, such as a dry composition. In a further embodiment, thepaste forming material is a dried paste, such as a lyophilized paste. Inanother and further embodiment, the paste forming material is in theform of a powder, or pressed powder. In another embodiment, the pasteforming material has a density between about 1 mg/ml to about 40 mg/ml,such as between 5 mg/ml to about 35 mg/ml, for example between about 10mg/ml to about 35 mg/ml.

Advantageously, the components are pre-loaded in the syringe andcontainers in predefined amounts and ratios. Thus, measurements ofcomponent amounts are avoided, and a predefined amount or volume ofpaste is rapidly, easily, and conveniently produced.

In an embodiment of the disclosure, the volume of paste formed in thesyringe is between 1-15 ml, more preferably between 6-12 ml, and mostpreferably between 7-10 ml, such as 8 ml.

It was found that the present disclosure may provide pastes that act asa haemostatic matrix, and further are especially efficient ashaemostatic matrix due to the composition, flowability, and rheology.

In an embodiment of the disclosure, the paste is a haemostatic paste.

Preferably, the paste formed is a flowable paste.

Base Receival

In the first configuration shown in FIG. 1 , the first and secondcontainers are mounted in the device, but not received at the base. Inthe second configuration shown in FIG. 2 and FIG. 7 , the first andsecond containers are received at the base, and the connections to theconduits of the base are formed. Advantageously, the receival of thefirst and second container at the base occurs simultaneously and suchthat the connection to conduits is formed essentially instantly, therebyreducing the risk of spillage and wasted drug and other materials.

Instant connection upon receival at the base may be obtained if the twocontainers each have a sealed opening. A sealed opening may be connectedinstantly by e.g. piercing or penetration. Thus advantageously, theseals are adapted to be pierced or penetrated.

The two sealed openings may be connected and pierced simultaneously by amanual push towards the base station, as illustrated in FIG. 2 . Uponpiercing the sealing, the connection to the container is created.

In an embodiment of the disclosure, the first container has a firstsealed opening, and the second container has a second sealed opening,and wherein the openings are configured to be received at the base. In afurther embodiment, the seals are adapted to be pierced.

To further facilitate simultaneous piercing of the first sealed openingand the second sealed opening, the first and second containers areadvantageously attached to each other such that the sealed openings arein the same plane as illustrated in FIGS. 1 and 6 .

In an embodiment of the disclosure, the first and second containers areattached to each other, such that the sealed openings are in the sameplane.

Advantageously, the conduits, or tubing, of the base are configured topierce the sealing of the containers, when the mounted containers arepushed into receival at the base. Thus, fast, instant, and reliablereceival at the base is obtained by applying a manual pressure (P) asillustrated in FIG. 2 .

In an embodiment of the disclosure, the first and second containers areconfigured to be received at the base by applying a pressure, such as amanual pressure.

To further enable simultaneous piercing of the first sealed opening andthe second sealed opening, it is advantageous that the first conduit andthe second conduit have at least a portion extending perpendicular tothe plane of the base, which is configured for piercing the seals. Theportions may be configured for piercing by having a pointed end forpenetrating the sealed openings, such as a needle shaped end. FIG. 1shows an embodiment, where the first conduit has at least one end 6 aconfigured for piercing a sealed opening, and the second conduit has atleast one end 6 b configured for piercing a sealed opening. Optionallyboth ends of the conduit may be configured for piercing sealed opening.

In an embodiment of the disclosure, the first conduit and the secondconduit have at least one portion extending perpendicular to the planeof the base. In a further embodiment, the at least one perpendicularportion of the conduits comprises a pointed end configured forpenetrating the sealed openings of the containers. In a furtherembodiment, the perpendicular portion of the conduits has a needleshape.

To minimize the risk of spillage and wasted drug and other materials, itmay be advantageous that the second container is received at the baseimmediately before the first container is received. Thus, the connectionto the second conduit is formed immediately before the connection to thefirst conduit, which ensures that the pressure driven force is notintroduced into the device before all connections are formed.

Receival of the second container at the base immediately before thefirst container may be obtained if a perpendicular portion of the firstconduit is shorter than a perpendicular portion of the second conduit,as illustrated in FIG. 1 .

In an embodiment of the disclosure, the perpendicular portion of thefirst conduit is shorter than the perpendicular portion of the secondconduit.

To obtain a compact device, and for easy and convenient receival of thecontainers at the base, the first conduit and the second conduitadvantageously each form a U-shaped tubing. An embodiment of a basecomprising U-shaped conduits is illustrated in FIG. 1 .

The first conduit forms a U, where the first end of the tube isconnected to the first container and the second end of the tube isconnected to the second container. To minimize the risk of spillage andwasted bioactive material and other materials, the second end of thetube is advantageously slightly longer than the first end of the tube.Thus, the second end of the tube may pierce the sealing of the of thesecond container, immediately before the first end of the tube piercesthe sealing of the first container.

The second conduit also forms a U, where the first end of the tubing isconnected to the second container, and the second end is connected tothe syringe. For easy receival of the second container at the base, thefirst end of the tubing has advantageously the same length as the secondend of first conduit, as illustrated in FIG. 1 .

Items

The presently disclosed may be described in further detail withreference to the following items.

-   -   1. A device (1) for reconstituting a bioactive agent and forming        a paste, the device comprising:        -   a base (2) configured for receiving:            -   a first container (3) containing a liquid (3 a), and            -   a second container (4) containing the bioactive agent (4                a),        -   a syringe (5) containing a paste forming material (5 a), the            syringe being attachable to the base,    -   wherein the base has a first conduit (6) for fluidly connecting        the first container with the second container and a second        conduit (7) for fluidly connecting the second container with the        syringe, and    -   wherein the first container is configured to be pressurizable        such that when the first and second containers are received at        the base, the liquid is forced through the first conduit into        the second container, thereby reconstituting the bioactive        agent, and the reconstituted bioactive agent is forced through        the second conduit into the syringe, such that a paste (5 c) is        formed.    -   2. The device according to item 1, wherein the paste forming        material comprises a biocompatible polymer.    -   3. The device according to any of the preceding items, wherein        the paste forming material comprises water-insoluble particles        and/or cross-linked particles.    -   4. The device according to any of the preceding items, wherein        the paste forming material comprises cross-linked gelatine        particles.    -   5. The device according to any of the preceding items, wherein        the paste forming material is in the form of a solid, such as a        dry composition.    -   6. The device according to any of the preceding items, wherein        the paste forming material is a dried paste, such as a        lyophilized paste.    -   7. The device according to any of the preceding items, wherein        the paste forming material is in the form of a powder, or        pressed powder.    -   8. The device according to any of the preceding items, wherein        the paste forming material has a density between about 1 mg/ml        to about 40 mg/ml, such as between 5 mg/ml to about 35 mg/ml,        for example between about 10 mg/ml to about 35 mg/ml.    -   9. The device according to any of the preceding items, wherein        the bioactive agent is a dried or lyophilized substance.    -   10. The device according to any of the preceding items, wherein        the bioactive agent comprises thrombin.    -   11. The device according to any of the preceding items, wherein        the bioactive agent comprises or consists of lyophilized        thrombin.    -   12. The device according to any of the preceding items, wherein        the liquid is a diluent.    -   13. The device according to any of the preceding items, wherein        the liquid is an aqueous medium selected from the group of:        water, glycerol, sterile water, saline, sterile saline, a        calcium chloride solution, a buffered aqueous solution, and        combinations thereof.    -   14. The device according to any of the preceding items, wherein        the first container is pressurized to between 0.1-5 bar, more        preferably between 1-3 bar, and most preferably about 1 bar.    -   15. The device according to any of the preceding items, wherein        the first container is pressurized by liquid pressure.    -   16. The device according to item 15, wherein the liquid is a        pressurized liquid.    -   17. The device according to any of the preceding items, wherein        the first container is pressurized by compression, optionally        elastic deformation.    -   18. The device according to item 17, comprising a collapsable        first container, and/or an elastic element, such as a spring,        adapted to control the volume of the first container.    -   19. The device according to any of the preceding items, wherein        the paste is a haemostatic paste.    -   20. The device according to any of the preceding items, wherein        the paste is flowable.    -   21. The device according to any of the preceding items, wherein        the volume of paste formed in the syringe is between 1-15 ml,        more preferably between 6-12 ml, and most preferably between        7-10 ml, such as 8 ml.    -   22. The device according to any of the preceding items, wherein        the syringe is detachably attached to the base by a locking        mechanism, such as a screw, click-on, slide-on, or snap-fit        locking mechanism.    -   23. The device according to any of the preceding items, wherein        the syringe further comprises a pressure controlling element.    -   24. The device according to item 23, wherein the pressure        controlling element is a filter adapted to filtrate fluids in        the gaseous state from fluids in the liquid state.    -   25. The device according to item 24, wherein the filter        comprises a composition adapted to be expandable upon contact        with water.    -   26. The device according to any of items 24-25, wherein the        filter comprises a hydrophobic material.    -   27. The device according to any of the preceding items, wherein        the first container has a first sealed opening, and the second        container has a second sealed opening, and wherein the openings        are configured to be received at the base.    -   28. The device according to item 27, wherein the seals are        adapted to be pierced.    -   29. The device according to any of the preceding items, wherein        the first and second container are attached to each other, such        that the sealed openings are in the same plane.    -   30. The device according to any of the preceding items, wherein        the first conduit and the second conduit have at least one        portion extending perpendicular to the plane of the base.    -   31. The device according to item 30, wherein the at least one        perpendicular portion of the conduits comprises a pointed end        configured for penetrating the sealed openings of the        containers.    -   32. The device according to item 31, wherein the perpendicular        portion of the conduits has a needle shape.    -   33. The device according to any of items 30-32, wherein the        perpendicular portion of the first conduit is shorter than the        perpendicular portion of the second conduit.    -   34. The device according to any of the preceding items, wherein        the first and second containers are configured to be received at        the base by applying a manual pressure.    -   35. A kit of parts for the device according to any of items        1-34, comprising a base, a syringe containing a paste forming        material, a first container containing a liquid, and a second        container containing a bioactive agent.    -   36. A method for reconstituting a bioactive agent and forming a        paste, the method comprising:        -   providing a first container (3) containing a liquid (3 a)            under positive pressure,        -   providing a second container (4) containing the bioactive            agent (4 a),        -   providing a syringe (5) containing a paste forming material            (5 a), and        -   fluidly connecting the first container with the second            container (6) and fluidly connecting the second container            with the syringe (7) such that the liquid is forced from the            first container into the second container, thereby            reconstituting the bioactive agent, and the reconstituted            bioactive agent is forced from the second container into the            syringe, such that a paste (5 c) is formed.    -   37. The method according to item 36, configured to be carried        out using the device according to any of items 1-34 or the kit        of parts according to item 35.    -   38. Use of the device according to any of items 1-34 or the kit        of parts according to item 35 for the method according to item        36.

REFERENCE NUMBERS

-   -   1—device    -   2—base    -   3—first container    -   3 a—first container liquid    -   3 b—first container opening    -   4—second container    -   4 a—second container bioactive agent    -   4 b—second container opening    -   4 c—reconstituted bioactive agent    -   5—syringe    -   5 a—syringe paste forming material    -   5 b—filter    -   5 c—paste    -   6—first conduit    -   6 a—first conduit end    -   7—second conduit    -   7 a—second conduit end

REFERENCES

-   [1] WO 10/043685.

The invention claimed is:
 1. A device for reconstituting a bioactiveagent and forming a paste, the device comprising: a first containercontaining a liquid, a second container containing the bioactive agent,a base configured for receiving the first and second container a syringecontaining a paste forming material, the syringe being attachable to thebase, wherein the base has a first conduit for fluidly connecting thefirst container with the second container and a second conduit forfluidly connecting the second container with the syringe, and whereinthe first container is configured to have positive pressure energystored such that when the first and second containers are received atthe base, the liquid is forced through the first conduit into the secondcontainer, thereby reconstituting the bioactive agent, and thereconstituted bioactive agent is forced through the second conduit intothe syringe, such that a paste is formed.
 2. The device according toclaim 1, wherein the paste forming material comprises a biocompatiblepolymer.
 3. The device according to claim 1, wherein the bioactive agentis a dried or lyophilized substance.
 4. The device according to claim 1,wherein the liquid is a diluent.
 5. The device according to claim 1,wherein the stored pressure energy of the first container is between0.1-5 bar.
 6. The device according to claim 1, wherein the storedpressure energy of the first container is obtained by gas pressurizingthe liquid.
 7. The device according to claim 6, wherein the liquid is agas pressurized liquid.
 8. The device according to claim 1, wherein thefirst container is pressurized by compression.
 9. The device accordingto claim 8, comprising a collapsable first container, and/or an elasticelement, element adapted to control the volume of the first container.10. The device according to claim 9, wherein the elastic element is asspring adapted to control the volume of the first container.
 11. Thedevice according to claim 1, wherein the paste is a haemostatic paste.12. The device according to claim 1, wherein the syringe furthercomprises a pressure controlling element.
 13. The device according toclaim 12, wherein the pressure controlling element is a filter adaptedto filtrate fluids in the gaseous state from fluids in the liquid state.14. The device according to claim 1, wherein the first container has afirst sealed opening, and the second container has a second sealedopening, and wherein the openings are configured to be received at thebase.
 15. The device according to claim 14, wherein the first and secondcontainer are attached to each other, such that the sealed openings arein the same plane.
 16. A kit of parts for the device according to claim1, comprising the base, the syringe containing a paste forming material,the first container containing a liquid, and the second containercontaining a bioactive agent.
 17. The device according to claim 1,wherein the first container is pressurized by elastic deformation. 18.The device according to claim 1, wherein the stored pressure energy ofthe first container is between 1-3 bar or about 1 bar.
 19. The deviceaccording to claim 1, wherein the first conduit and the second conduithave at least one portion extending perpendicular to a plane of thebase.
 20. A method for reconstituting a bioactive agent and forming apaste, the method comprising: providing a first container containing aliquid configured to have positive pressure energy stored; providing asecond container containing the bioactive agent; providing a syringecontaining a paste forming material; and fluidly connecting the firstcontainer with the second container and fluidly connecting the secondcontainer with the syringe such that the liquid is forced from the firstcontainer into the second container, thereby reconstituting thebioactive agent, and the reconstituted bioactive agent is forced fromthe second container into the syringe, such that a paste is formed.